MILK THISTLE

BACKGROUND

Ingredient Type: Botanical, Extract

Also Known As: Silybum marianum extract, Silymarin, Mary thistle extract, Holy thistle extract

Silybum marianum or milk thistle is a plant from the Asteraceae family, native to Southern Europe, parts of the Middle East, and Northern Africa. It has been naturalized in South America, North America, and Southern Australia and requires warm, dry soil to grow (1).  Milk thistle is considered a weed by most gardeners because of how fast it grows.  Milk thistle can grow to be over 10 feet tall and is covered with spines.  It also grows purples flower which can contain 190 seeds each (2).

Silymarin, which is the most active component in milk thistle, is extracted from the seeds of the milk thistle plant and is made up of compounds known as flavonolignans. The compounds in the flavonolignans include silibin A, silibin B, taxifolin, isosilibin A, isosilibin B, silichristin A, silidianin (3).

TRADITIONAL USES

Milk thistle has been used for over 2,000 years. In ancient Greece, Dioscorides wrote in his book about approximately 600 medicinal plants and herbs that milk thistle tea was used as a remedy for snakebites.  In the Middle Ages, people used milk thistle to treat different liver problems.

In the 1500s, John Gerard wrote that milk thistle could help with depression and emotional distress. At this time, people used the whole plant, including the roots and milk. Later, a famous physician and herbalist named Nicolas Culpeper claimed that milk thistle could help “unblock” the liver and even help cure jaundice.

Milk thistle was also used to help treat irregular menstruation, varicose veins, kidney, liver and spleen problems (2).

WHAT DOES SCIENCE TELL US?

Milk Thistle Seed Extract Might Help Support a Healthy Liver:

In a few studies, researchers looked at the effects that milk thistle has on liver fibrosis.  Part of the liver fibrosis process occurs when hepatic parenchymal cells proliferate, and hepatic stellate cells are converted into myofibroblast. The milk thistle extract blocks some cellular pathways and protein signals that cause such proliferation and slows down the activation of the hepatic stellate cells. It is noteworthy that these studies were conducted on animals and human clinical trials are required (1,4,5).

Milk thistle occupies binding sites of liver cells that aids in the prevention of toxins being absorbed by the cell and into the liver. Milk thistle can also block proteins that transport the toxins within the membrane to the liver cells, to reduce the hepatotoxic effects of chemicals and drugs (6). Research shows that milk thistle may be useful in treating chemotherapy-related toxicity in children (7). There is also evidence that milk thistle extract can be used to treat hepatotoxicity from poisonous mushrooms (8). Research shows that milk thistle combined with aloe vera had hepatoprotective effects again liver injury caused by acute and chronic carbon tetrachloride poisoning (9).

In another study, researchers investigated the use of milk thistle extract on patients with non-alcoholic fatty liver disease, measuring its effects on metabolic, hepatic and anti-inflammatory concerns. Results showed positive effects of milk thistle (10). Further studies showed that milk thistle along with vitamin E and a hypocaloric diet improved fatty liver index and hepatic test functions (which usually include blood levels of total protein, albumin, bilirubin, and liver enzymes) (11,12,13). In a randomized, double-blind, placebo-controlled trial of adults with non-alcoholic steatohepatitis, a more severe form of non-alcoholic fatty liver disease, researchers did not find scientifically significant evidence that milk thistle provided reduced non-alcoholic steatohepatitis scores when compared to the placebo but did see a small reduction warranting the need for further research (14).

Milk Thistle Seed Extract Possibly Has Anti-inflammatory Effects:

Inflammation occurs when blood platelets are activated by cyclooxygenase (COX), causing thrombotic platelet activity and pro-inflammatory mediators to be produced (15).  Research has shown that milk thistle can inhibit the COX pathway and as such, the antioxidant activity of milk thistle can be credited to its both free radical scavenging and lipid peroxidation inhibitors (15).

Milk thistle extract in combination with Praziquantel, which is a drug of choice in treating schistosomiasis, can have anti-inflammatory and anti-fibrotic effects in a study done with mice (16).

Some human clinical trials showed that milk thistle has no effect on the treatment of alcoholic liver diseases, and as such, more research is required to support the use of milk thistle in alcoholic liver diseases (17,18,19).

Milk Thistle Seed Extract Possibly Has Antioxidant Effects:

Research shows that milk thistle has protective effects on DNA, protein, and lipid oxidation damage. Milk thistle extract was found to have a protective effect against DNA, protein and lipid oxidation by acting as an inhibitor against hydroxyl radical-induced DNA, protein and lipid damage (20).

Milk Thistle Seed Extract Possibly Has an Immunomodulatory Effect:

Several studies have indicated that milk thistle can be a valuable therapeutic agent for immune system modulation and regulation due to inhibitory and proliferation properties on certain cells and pathways (21,22,23,24). Researchers suggested that more clinical trials with human participants would be valuable.

In liver cancer research on the effects of milk thistle on hepatocellular carcinoma in mice, researchers found that milk thistle can be a potential inhibitor of hepatocellular carcinoma cell growth. The hepatocellular carcinoma cells target the Notch pathway, which is a signaling pathway among cells in the body. If the Notch pathway is altered in any way by the hepatocellular carcinoma cells, there is a significant progression of the cancer. Research has shown that milk thistle can inhibit those cells from altering the Notch pathway, and thus reduce the progression of the cancer (25).  Further research showed comparable results of milk thistle on the biological mechanism of cancers with regard to cell and pathway inhibition properties; however, researchers pointed out that further investigation into these mechanisms is necessary (26,27,28).

In animals, specifically, baboons, milk thistle was found to slow the development of alcohol-induced hepatic fibrosis by preventing collagen type I and decreasing histological progression of fibrosis (5). Another study on rats showed that milk thistle’s effect of mitigating lipid peroxidation and inhibiting the expression of the NF-κB (a proinflammatory signaling pathway) could protect against alcohol-induced liver injury (29). Further research in rats showed that milk thistle extract inhibits cytochrome p4502E1 (which metabolizes potential cytotoxic and carcinogenic agents) and ethanol metabolism in hepatocellular carcinoma cells. Additionally, researchers found that the milk thistle inhibited hepatocellular carcinoma cell proliferation that is ethanol-dependent (30).

Research showed that the inhibitory properties of milk thistle can be helpful in the treatment of hepatitis C virus. One study found that the compounds in milk thistle were able to inhibit the

RNA-dependent RNA polymerase activity found in the hepatitis C virus.  Consequently, the researchers suggested that milk thistle could possibly be developed as an antiviral for the hepatitis C virus.  A couple studies found that intravenous milk thistle extract was well tolerated in individuals after liver transplantation as a means to stop the recurrence of hepatitis C, but researchers called for longer treatment times to be studied further (31,32).

On the other hand, one clinical trial conducted in an Egyptian village over a 12-month period and with 177 patients who had chronic hepatitis C found that there was no effect from milk thistle on the virus. The researchers did conclude that milk thistle was safe to consume for a period of 1 year and suggested further research be conducted (33). Similarly, several clinical trials reported that there was not enough statistically significant evidence that milk thistle extract is effective in antiviral treatment of hepatitis C virus in patients who were previously treated with interferon therapy.  Researchers suggested that further research with higher doses and at less advanced stages of the disease should be conducted (34,35,36,37).

One clinical trial investigated the treatment of persons who were diagnosed with non-alcoholic fatty liver disease and hepatitis C virus. Researchers found that silybin from milk thistle in addition to phosphatidylcholine and vitamin E resulted in an improvement of liver enzymes, insulin resistance, and liver histology without an increase in body weight (37).

SAFETY

Interactions:

Moderate

• May interact with medications that are changed by the liver such as cytochrome P450 2C9 substrates and glucuronidated drugs

Minor

• May decrease effectiveness of estrogen pills
• May change amount of cholesterol-lowering medications used

Side-Effects:

• Milk thistle appears to be well tolerated in recommended doses of 240 to 900 mg a day in divided doses. Higher doses and prolonged use may produce headaches and itching, a laxative effect and occasional gastrointestinal effects, such as nausea and diarrhea, may occur (38,39,40,41).
• Milk thistle may produce allergic reactions, which tend to be more common among people who are allergic to plants in the same family (for example, ragweed, chrysanthemum, marigold, and daisy) (42).

REFERENCES

1. Abenavoli L, Capasso R, Milic N, Capasso F. Milk thistle in liver diseases: past, present, future. Phytother Res. 2010;24(10):1423-1432. doi:10.1002/ptr.3207
2. “Milk Thistle History.” Milk Thistle Resource, www.milkthistleresource.com/milk-thistle-history/. Accessed June 8, 2018.
3. Kazazis CE, Evangelopoulos AA, Kollas A, Vallianou NG. The therapeutic potential of milk thistle in diabetes. Rev Diabet Stud. 2014;11(2):167-174. doi:10.1900/RDS.2014.11.167
4. Jia JD, Bauer M, Cho JJ, et al. Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen α1(I) and TIMP-1. J Hepatol. 2001;35(3):392-398. doi:10.1016/S0168-8278(01)00148-9
5. Lieber CS, Leo MA, Cao Q, Ren C, DeCarli LM. Silymarin retards the progression of alcohol-induced hepatic fibrosis in baboons. J Clin Gastroenterol. 2003;37(4):336-339. doi:10.1097/00004836-200310000-00013
6. Federico A, Dallio M, Loguercio C. Silymarin/Silybin and chronic liver disease: A marriage of many years. Molecules. 2017;22(2). doi:10.3390/molecules22020191
7. Ladas EJ, Kroll DJ, Oberlies NH, et al. A randomized, controlled, double-blind, pilot study of milk thistle for the treatment of hepatotoxicity in childhood acute lymphoblastic leukemia (ALL). Cancer. 2010;116(2):506-513. doi:10.1002/cncr.24723
8. Mengs U, Torsten Pohl R-, Mitchell T. Legalon® SIL: The Antidote of Choice in Patients with Acute Hepatotoxicity from Amatoxin Poisoning. Curr Pharm Biotechnol. 2012;13(10):1964-1970. doi:10.2174/138920112802273353
9. Kim S-H, Cheon HJ, Yun N, et al. Protective effect of a mixture of Aloe vera and Silybum marianum against carbon tetrachloride-induced acute hepatotoxicity and liver fibrosis. J Pharmacol Sci. 2009;109(1):119-127. doi:10.1254/jphs.08189FP
10. Cacciapuoti F, Scognamiglio A, Palumbo R, Forte R, Cacciapuoti F. Silymarin in nonalcoholic fatty liver disease. World J Hepatol. 2013;5(3):109-113. doi:10.4254/wjh. v5.i3.109
11. Aller R, Izaola O, Gómez S, et al. Effect of silymarin plus Vitamin E in patients with non-alcoholic fatty liver disease. A randomized clinical pilot study. Eur Rev Med Pharmacol Sci. 2015;19(16):3118-3124.
12. Hajiaghamohammadi AA, Ziaee A, Oveisi S, Masroor H. Effects of metformin, pioglitazone, and silymarin treatment on non-alcoholic fatty liver disease: A randomized controlled pilot study. Hepat Mon. 2012;12(8). doi:10.5812/hepatmon.6099
13. Solhi H, Ghahremani R, Kazemifar AM, Yazdi ZH. Silymarin in treatment of non-alcoholic steatohepatitis: A randomized clinical trial. Casp J Intern Med. 2014;5(1):9-12.
14. Chan W-K, Nik Mustapha NR, Mahadeva S. A Randomized Trial of Silymarin for the Treatment of?Nonalcoholic Steatohepatitis. Clin Gastroenterol Hepatol. 2017;15(12):1940-1949.e8. doi: 10.1016/j.cgh.2017.04.016
15. Bijak M, Saluk-Bijak J. Flavonolignans inhibit the arachidonic acid pathway in blood platelets. BMC Complement Altern Med. 2017;17(1). doi:10.1186/s12906-017-1897-7
16. El-Lakkany NM, Hammam OA, El-Maadawy WH, Badawy AA, Ain-Shoka AA, Ebeid FA. Anti-inflammatory/anti-fibrotic effects of the hepatoprotective silymarin and the schistosomicide praziquantel against Schistosoma mansoni-induced liver fibrosis. Parasites and Vectors. 2012;5(1). doi:10.1186/1756-3305-5-9
17. Rambaldi A, Jacobs BP, Gluud C. Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Cochrane Database Syst Rev. 2007;(4). doi:10.1002/14651858.CD003620.pub3
18. The Korean Association for the Study of the Liver (KASL). KASL Clinical Practice Guidelines: Management of Alcoholic Liver Disease. Clinical and molecular hepatology. 2013;19(3):216-254. doi:10.3350/cmh.2013.19.3.216.
19. Parés A, Planas R, Torres M, et al. Effects of silymarin in alcoholic patients with cirrhosis of the liver: Results of a controlled, double-blind, randomized and multicenter trial. J Hepatol. 1998;28(4):615-621. doi:10.1016/S0168-8278(98)80285-7
20. Serçe A, Toptanci BÇ, Tanrikut SE, et al. Assessment of the antioxidant activity of Silybum marianum seed extract and its protective effect against DNA oxidation, protein damage and lipid peroxidation. Food Technol Biotechnol. 2016;54(4). doi:10.17113/ftb.54.04.16.4323
21. Wilasrusmee C, Kittur S, Shah G, et al. Immunostimulatory effect of Silybum Marianum (milk thistle) extract. Med Sci Monit. 2002;8(11):BR439-43.
22. Esmaeil N, Anaraki SB, Gharagozloo M, Moayedi B. Silymarin impacts on immune system as an immunomodulator: One key for many locks. Int Immunopharmacol. 2017;50:194-201. doi:10.1016/j.intimp.2017.06.030
23. Gharagozloo M, Jafari S, Esmaeil N, Javid EN, Bagherpour B, Rezaei A. Immunosuppressive Effect of Silymarin on Mitogen-Activated Protein Kinase Signalling Pathway: the Impact on T Cell Proliferation and Cytokine Production. Basic Clin Pharmacol Toxicol. 2013;113(3):209-214. doi:10.1111/bcpt.12088
24. Gharagozloo M, Karimi M, Amirghofran Z. Immunomodulatory effects of silymarin in patients with β-thalassemia major. Int Immunopharmacol. 2013;16(2):243-247. doi:10.1016/j.intimp.2013.04.016
25. Zhang S, Yang Y, Liang Z, et al. Silybin-mediated inhibition of notch signaling exerts antitumor activity in human hepatocellular carcinoma cells. PLoS One. 2013;8(12). doi:10.1371/journal.pone.0083699
26. Ghasemi R, Ghaffari SH, Momeny M, et al. Multitargeting and antimetastatic potentials of silibinin in human HepG-2 and PLC/PRF/5 hepatoma cells. Nutr Cancer. 2013;65(4):590-599. doi:10.1080/01635581.2013.770043
27. Varghese L, Agarwal C, Tyagi A, Singh RP, Agarwal R. Silibinin efficacy against human hepatocellular carcinoma. Clin Cancer Res. 2005;11(23):8441-8448. doi:10.1158/1078-0432.CCR-05-1646
28. Momeny M, Khorramizadeh MR, Ghaffari SH, et al. Effects of silibinin on cell growth and invasive properties of a human hepatocellular carcinoma cell line, HepG-2, through inhibition of extracellular signal-regulated kinase 1/2 phosphorylation. Eur J Pharmacol. 2008;591(1-3). doi:10.1016/j.ejphar.2008.06.011
29. Zhang W, Hong R, Tian T. Silymarin’s Protective Effects and Possible Mechanisms on Alcoholic Fatty Liver for Rats. Biomol Ther (Seoul). 2013;21(4):264-269. doi:10.4062/biomolther.2013.020
30. Brandon-Warner E, Sugg JA, Schrum LW, McKillop IH. SILIBININ INHIBITS ETHANOL METABOLISM AND ETHANOL-DEPENDENT CELL PROLIFERATION IN AN IN VITRO MODEL OF HEPATOCELLULAR CARCINOMA. Cancer letters. 2010;291(1):120-129. doi:10.1016/j.canlet.2009.10.004.
31. Mariño Z, Crespo G, D’Amato M, et al. Intravenous silibinin monotherapy shows significant antiviral activity in HCV-infected patients in the peri-transplantation period. J Hepatol. 2013;58(3):415-420. doi:10.1016/j.jhep.2012.09.034
32. Eurich D, Bahra M, Berg T, et al. Treatment of hepatitis C-virus-reinfection after liver transplant with silibinin in nonresponders to pegylated interferon-based therapy. Exp Clin Transplant. 2011;9(1):1-6.
33. Tanamly MD, Tadros F, Labeeb S, et al. Randomised double-blinded trial evaluating silymarin for chronic hepatitis C in an Egyptian village: Study description and 12-month results. Dig Liver Dis. 2004;36(11):752-759. doi:10.1016/j.dld.2004.06.015
34. Par A, Roth E, Miseta A, et al. [Effects of supplementation with the antioxidant flavonoid, silymarin, in chronic hepatitis C patients treated with peg-interferon + ribavirin. A placebo-controlled double blind study]. Az antioxidans flavonoid silymarin szupplementacioja hatasanak placebokontrollos Vizsg PEG-IFN + ribavirin antiviralis Kez reszesulo Kron C-hepatitises Bet. 2009;150(2):73-79. doi:10.1556/OH.2009.28517
35. Fried MW, Navarro VJ, Afdhal N, et al. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. Jama. 2012;308(3):274-282. doi:10.1001/jama.2012.8265
36. Yakoot M, Salem A. Spirulina platensis versus silymarin in the treatment of chronic hepatitis C virus infection. A pilot randomized, comparative clinical trial. BMC Gastroenterol. 2012;12. doi:10.1186/1471-230X-12-32
37. Hawke RL, Schrieber SJ, Soule TA, et al. Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. J Clin Pharmacol. 2010;50(4):434-449. doi:10.1177/0091270009347475
38. Loguercio C, Festi D. Silybin and the liver: From basic research to clinical practice. World J Gastroenterol. 2011;17(18):2288-2301. doi:10.3748/wjg.v17.i18.2288
39. Gordon A, Hobbs D a, Bowden DS, et al. Effects of Silybum marianum on serum hepatitis C virus RNA, alanine aminotransferase levels and well-being in patients with chronic hepatitis C. J Gastroenterol Hepatol. 2006;21(1 Pt 2):275-280. doi:10.1111/j.1440-1746.2006. 04138.x
40. Müzes G, Deák G, Láng I, Nékám K, Niederland V, Fehér J. Effect of Silimarin (Legalon) Therapy on the Antioxidant Defense Mechanism and Lipid Peroxidation in Alcoholic Liver Disease (Double Blind Protocol). 1990 Apr 22;131(16):863-6.
41. Lucena MI, Andrade RJ, de la Cruz JP, Rodriguez-Mendizabal M, Blanco E, Sánchez de la Cuesta F. Effects of silymarin MZ-80 on oxidative stress in patients with alcoholic cirrhosis. Results of a randomized, double-blind, placebo-controlled clinical study. Int J Clin Pharmacol Ther. 2002;40(1):2-8.
42. Milk Thistle. NCCIH. 2018. https://nccih.nih.gov/health/milkthistle/ataglance.htm. Accessed February 28, 2018.

See the Penn State Hershey Health Information Library entry for milk thistle, the National Center for Complementary and Integrative Health entry for milk thistle, this European Medicines Agency monograph on Silybum marianum, the Examine.com entry for milk thistle, or the Drugs.com entry for milk thistle for more information.